The major themes of this project are (a) linkage of laboratory observations with clinically relevant data in a systematic Fashion and (b) exploration of mechanism-based new approaches to therapy in CLL. Available databases and cell banks will be expanded in a carefully coupled fashion to optimize the translational element of the research. New approaches to therapy with unique exploitable mechanisms of action will be explored. The clinical endpoints will be related specifically to pharmacodynamic, cell death and genetic measurements in these protocols. Aim 1 a) To prospectively collect relevant clinical data at the time when cell and serum samples are sent to laboratory investigators or banks. b) To study the emergence of new prognostic factors as CLL progresses. c) To correlate molecular, genetic, cell death, and immunologic data with clinical events. We will use this data to develop a model of CLL as a genetically-driven, evolving, dedifferentiating disease. d) To study the prognostic impact of clinical and laboratory data using multivariate modeling techniques. Aim 2 a) To develop treatment of paradigms with the goal of achieving true complete remissions in CLL (PCR negative for Ig gene rearrangement). b) To develop efficient phase II clinical trials of new agents coupled with pharmacodynamic and mechanistic studies. c) To introduce new agents with unique mechanisms of action into phase I clinical trials in CLL. Aim 3 To develop a comprehensive profile of molecular events and protein expression exposure profiles on patients with CLL at different phases of the disease. Prognostic significance for response to therapy and survival will be sought.